chr5-176295144-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001308195.2(SIMC1):​c.1546C>T​(p.Pro516Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SIMC1
NM_001308195.2 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.409
Variant links:
Genes affected
SIMC1 (HGNC:24779): (SUMO interacting motifs containing 1) Enables SUMO polymer binding activity and peptidase inhibitor activity. Predicted to be involved in negative regulation of peptidase activity. Located in sarcomere. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23891282).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIMC1NM_001308195.2 linkc.1546C>T p.Pro516Ser missense_variant Exon 3 of 10 ENST00000429602.7 NP_001295124.1 Q8NDZ2-5B4DRM7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIMC1ENST00000429602.7 linkc.1546C>T p.Pro516Ser missense_variant Exon 3 of 10 1 NM_001308195.2 ENSP00000410552.3 Q8NDZ2-5

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250742
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135532
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461466
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
727028
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 23, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.244C>T (p.P82S) alteration is located in exon 2 (coding exon 2) of the SIMC1 gene. This alteration results from a C to T substitution at nucleotide position 244, causing the proline (P) at amino acid position 82 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.039
.;.;T;T
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Benign
0.45
N
LIST_S2
Uncertain
0.90
D;.;D;D
M_CAP
Benign
0.0075
T
MetaRNN
Benign
0.24
T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.5
.;.;L;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.2
D;D;N;D
REVEL
Benign
0.17
Sift
Benign
0.26
T;T;T;T
Sift4G
Benign
0.92
T;T;T;T
Polyphen
0.97
D;D;D;.
Vest4
0.39
MutPred
0.29
.;.;Loss of loop (P = 0.0235);.;
MVP
0.46
MPC
2.1
ClinPred
0.95
D
GERP RS
4.2
Varity_R
0.068
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1345347726; hg19: chr5-175722147; API